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<p>CDK2 is a principal mediator of CDK4/6 resistance. Concurrent CDK2/4/6 blockade may be effective in treating HR-positive, HER2-negative advanced breast cancer (ABC). This randomized, double-blind, parallel-controlled, phase 3 trial (ClinicalTrials.gov, NCT05375461) assessed the efficacy of culmerciclib, a CDK2/4/6 inhibitor, plus fulvestrant in ABC. Patients with HR-positive, HER2-negative, locally recurrent or metastatic breast cancer were randomized (2:1) to receive culmerciclib plus fulvestrant or matching placebo plus fulvestrant. Between March 18, 2022 and March 3, 2023, 293 pretreated patients (median age 53.0 years; pre- or perimenopausal 42.3%; bone metastasis 65.2%) were randomized to assigned treatments. At this prespecified interim analysis, culmerciclib plus fulvestrant extended the median investigator-assessed progression-free survival (PFS) significantly, the primary endpoint, as compared with placebo plus fulvestrant (16.6 months, 95% CI 13.8 to not evaluable <i>versus</i> 7.5 months, 95% CI 5.3 to 11.0; hazard ratio 0.36, 95% CI 0.26–0.51; stratified log rank test <i>P</i> &lt; 0.001). Consistent effects were observed across diverse subgroups of patients. At a median follow-up duration of 13.8 months, overall survival was immature. The investigators-assessed objective response rate was 40.2% (95% CI, 33.3–47.5) for culmerciclib compared to 12.1% (95% CI 6.4–20.2) for placebo (stratified Mantel-Haenszel χ<sup>2</sup> test <i>P</i> &lt; 0.001). Diarrhea (87.1%) and neutropenia (80.4%) were the most common toxicities with culmerciclib plus fulvestrant. In conclusion, this randomized clinical trial met its primary outcome. Culmerciclib plus fulvestrant is well tolerated and leads to a significant gain in PFS of pretreated HR-positive HER2-negative ABC patients.</p>

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Novel CDK2/4/6 inhibitor culmerciclib (TQB3616) plus fulvestrant in previously treated, HR-positive, HER2-negative advanced breast cancer: a randomized, double-blind, phase 3 trial

  • 期刊论文

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  • 发表日期：

    2025年12月18日

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  • Yongmei Yin,
  • Qingyuan Zhang,
  • Tao Sun,
  • Chunfang Hao,
  • Zhihong Wang,
  • Jin Yang,
  • Yongsheng Wang,
  • Yanxia Shi,
  • Jing Sun,
  • Quchang Ouyang,
  • Haichuan Su,
  • Jinsheng Wu,
  • Lu Gan,
  • Meng Han,
  • Liming Gao,
  • Xiaojia Wang,
  • Bing Zhao,
  • Hui Li,
  • Jiuda Zhao,
  • Hongwei Yang,
  • Fangling Ning,
  • Fuguo Tian,
  • Juliang Zhang,
  • Hongmei Sun,
  • Zhaofeng Niu,
  • Hong Zong,
  • Aimin Zang,
  • Xinshuai Wang,
  • Xinyu Qian,
  • Shikai Wu,
  • Jianyun Nie,
  • Lijia He,
  • Ying Cheng,
  • Yanrong Hao,
  • Yi Zhai,
  • Huiping Li,
  • Jingfen Wang,
  • Shihong Wei,
  • Man Li,
  • Yunjiang Liu,
  • Hongqiang Guo,
  • Qun Hu,
  • Lina Liu,
  • Xinghua Han,
  • Ruizhen Luo,
  • Mingli Ni,
  • Xianjun Tang,
  • Zhenhua Zhai,
  • Meiqian Ding,
  • Haibo Wang,
  • Peng Shen,
  • Xian Wang,
  • Lian Liu,
  • Wenyan Chen,
  • Gang Liu,
  • Zhengwen Cai,
  • Zefei Jiang

摘要

CDK2 is a principal mediator of CDK4/6 resistance. Concurrent CDK2/4/6 blockade may be effective in treating HR-positive, HER2-negative advanced breast cancer (ABC). This randomized, double-blind, parallel-controlled, phase 3 trial (ClinicalTrials.gov, NCT05375461) assessed the efficacy of culmerciclib, a CDK2/4/6 inhibitor, plus fulvestrant in ABC. Patients with HR-positive, HER2-negative, locally recurrent or metastatic breast cancer were randomized (2:1) to receive culmerciclib plus fulvestrant or matching placebo plus fulvestrant. Between March 18, 2022 and March 3, 2023, 293 pretreated patients (median age 53.0 years; pre- or perimenopausal 42.3%; bone metastasis 65.2%) were randomized to assigned treatments. At this prespecified interim analysis, culmerciclib plus fulvestrant extended the median investigator-assessed progression-free survival (PFS) significantly, the primary endpoint, as compared with placebo plus fulvestrant (16.6 months, 95% CI 13.8 to not evaluable versus 7.5 months, 95% CI 5.3 to 11.0; hazard ratio 0.36, 95% CI 0.26–0.51; stratified log rank test P < 0.001). Consistent effects were observed across diverse subgroups of patients. At a median follow-up duration of 13.8 months, overall survival was immature. The investigators-assessed objective response rate was 40.2% (95% CI, 33.3–47.5) for culmerciclib compared to 12.1% (95% CI 6.4–20.2) for placebo (stratified Mantel-Haenszel χ2 test P < 0.001). Diarrhea (87.1%) and neutropenia (80.4%) were the most common toxicities with culmerciclib plus fulvestrant. In conclusion, this randomized clinical trial met its primary outcome. Culmerciclib plus fulvestrant is well tolerated and leads to a significant gain in PFS of pretreated HR-positive HER2-negative ABC patients.